The present invention relates to pharmaceutical compositions comprising enantiomerically pure R-NSAIDs and the methods of their use for the treatment of inflammation. Preferably, the R-NSAID used is R-flurbiprofen which is administered in a dose of at least 2.5 milligrams per kilogram of body weight per day.
Nonsteriodal anti-inflammatory drugs (NSAIDs) have been in use for over a century beginning with aspirin. In recent decades the arylpropionic acid (APA) class of these drugs has gained wide acceptance.
Although the NSAIDs are known to be effective against pain and inflammation, there are often severe side effects and toxicity associated with chronic use of these drugs. Chronic NSAID use is known to cause gastric and duodenal ulceration, which may be severe enough to result in significant morbidity and mortality. Furthermore, NSAID use has been reported to be associated with renal and hepatic toxicities, increase in bleeding times due to disruption of platelet function, prolongation of gestation due to uterine effects, and a decreased white cell count in the blood. Because of the side effects and toxicity, many NSAIDs are no longer in use in human medicine as analgesics. Some of these include tiaprofenic acid, suprofen, carprofen, pirprofen, benoxaprofen, and indoprofen.
Some NSAIDs, including the APAs, exhibit molecular chirality and thus have R- and S-enantiomers. The APAs, with the exception of naproxen, are currently prescribed as racemates.
For a given NSAID, there can be a difference in the properties exhibited by the R- and S-enantiomers. One important difference relates to the activities of the two enantiomers in connection with prostaglandin synthesis.
Prostaglandins are autocoids, produced by the body, which serve a variety of functions. An important step in the biosynthesis of prostaglandins requires the use of two cyclooxygenase (COX) enzymes, COX-1 or COX-2. COX-1 is present throughout the body and makes the prostaglandins that, among other things, help keep the stomach lining intact and the aid proper function of the kidneys. COX-2 is made by the body only under certain conditions, such as in response to tissue injury, and the prostaglandins produced by it are associated with pain and inflammation.
Researchers found that the S-enantiomers of NSAIDs were much better at inhibiting prostaglandin synthesis than the R-enantiomer, having 15-100 or even 500 times higher prostaglandin synthetase inhibitory activities than the R-enantiomers in the rat. Yamaguchi et al., Nippo Yakurigaku Zasshi, 90:295-302 (1987). Thus, it was thought that the biological activity of NSAIDs resided principally if not only in the S-enantiomers. Some researchers went as far as to say that xe2x80x9cat best, the R-isomers [of APAs] function as prodrugs for the therapeutically active S-formsxe2x80x9d when the racemic drug is administered to the host, and that the R-enantiomers are xe2x80x9cundesirable impurities in the active drug.xe2x80x9d Caldwell et al., Biochem. Pharmacol. 37:105-114 (1988).
Although the S-NSAIDs have the desired effect of inhibiting production of prostaglandins through the COX-2 pathway, they also inhibit the production through the COX-1 pathway and thus the bad side effects of NSAID use generally are also associated with the use of S-enantiomers.
Earlier studies by researchers in this field, as well as by the inventor himself, found that R-NSAIDs had little or no inhibiting effect on COX enzymes and prostaglandin production. What little anti-inflammatory effect existed was either found to be statistically insignificant or attributed to the S-enantiomer, the presence of which was due to either an enantiomerically impure dose of R-NSAID or inversion of the R-enantiomer in vivo. See K. Brune et al, Pure Enantiomers of 2-Arylpropionic Acids: Tools in Pain Research and Improved Drugs in Rheumatology, J. Clin. Pharmacol. 32:944-52, 946 (1992); K. Brune et al., Aspirin-like drugs may block pain independently of prostaglandin synthesis inhibition, Experentia 47:257-61, 260 (1991); U.S. Pat. No. 5,200,198 to Geisslinger et al.; and U.S. Pat. No. 5,206,029 to Brune et al.
Although the researchers did not find significant anti-inflammatory activity, there was evidence of other activity attributable to the R-enantiomer, such as amelioration of pain (see U.S. Pat. Nos. 5,200,198 and 5,206,029), treatment and prevention of cancer (see Wechter et al., R-Flurbiprofen Chemoprevention and Treatment of Intestinal Adenomas in the APCmin/+Mouse Model, Cancer Research 57:4316-24 (1997)), treatment of cystic fibrosis (see U.S. Pat. No. 5,981,592) and treating or delaying the onset of Alzheimer""s Disease (see U.S. Pat. No. 6,160,018).
U.S. Pat. Nos. 5,200,198 and 5,206,029 disclose the use of mixtures of R- and S-flurbiprofen to treat diseases characterized by pain and/or inflammation. The inventors state that R-flurbiprofen has better pain amelioration activity than S-flurbiprofen, and that the known side effects are coupled with the anti-inflammatory effects in S-flurbiprofen. Thus, according to the inventions, if one were to create a medicament for the treatment of a disease that was characterized primarily by pain, one would use a mixture having an excess of the R-flurbiprofen, so as to maximize the effects against pain. The amount of S-flurbiprofen in the mixture would be minimized, so as to attain a balance between the needed anti-inflammatory activity and the undesired side effects which result from use of the S-enantiomer. If, according to the disclosures of the ""198 and ""029 patents, one wanted to create medicament for the treatment of a disease characterized by both pain and inflammation, one would increase the amount of S-flurbiprofen in the composition in order to have the needed anti-inflammatory effect and would have to accept the unwanted side effects.
A common test which is used to determine whether a compound has activity as an anti-inflammatory drug is the carrageenan paw test. In this test, the test compound is administered to several rats. Thereafter, a paw on each rat is injected with a solution of carrageenan in order to induce edema in the paw as a measure of inflammation. After three hours, the volume of the paw is measured using a plethysmometer. Reduction of edema by 30% or more, as compared to a control group which was not given the test compound, is considered indicative of anti-inflammatory activity.
In the ""198 and ""029 patents, there is described the results of the carrageenan paw test done using a dosage of 0.3 mg/kg of R- or S-flurbiprofen. The enantiomeric purity of the compounds used is not disclosed. For these tests, it was reported that the reduction of edema for the S-flurbiprofen was 64%, indicating anti-inflammatory activity, but for the R-flurbiprofen it was only 18% which does not indicate anti-inflammatory activity.
The inventors in the ""198 and ""029 patents, Brune and Geisslinger, later reported carrageenan paw tests using dosages of approximately 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, and 2.5 mg/kg of R- and S-flurbiprofen (Experentia, 47:257-261). Only at the highest dose, 2.5 mg/kg, did the R-flurbiprofen demonstrate a statistically significant reduction in inflammation. In a 1996 article entitled New Insights into the Site and Mode of Antinociceptive Action of Flurbiprofen Enantiomers (J. Clin. Pharmcol. 36:513-20), Brune and Geisslinger discussed the tests first reported in the Experentia article, stating that: xe2x80x9cas expected, only the S-enantiomer had anti-inflammatory activity. The anti-inflammatory effects after administration of higher doses of R-flurbiprofen may be explained by an S-impurity of the administered R-enantiomer (purity: S-flurbiprofen, 98.5%; R-flurbiprofen, 99.1%) and/or by small amounts of S-flurbiprofen formed by inversion.xe2x80x9d
More recently, following the discovery of the differences between COX-1 and COX-2, some drug companies have set forth to make compounds which selectively inhibit COX-2, so as to achieve the desired anti-inflammatory and analgesic effects while avoiding the toxic effects associated with COX-1 inhibition. Some of these recent advances were discussed in a recent article in Science (Elizabeth Pennisi, xe2x80x9cBuilding A Better Aspirinxe2x80x9d, Science 280:1191-92 (1988), and have even found their way to the mainstream media such as Jerome Groopman""s article entitled xe2x80x9cSuperaspirinxe2x80x9d (The New Yorker p.32-35 (1998)). These articles present the new COX-2 inhibitor drugs as far superior to the older NSAIDs and state that this new class of COX-2 inhibitors will eventually replace the older NSAIDs, which will xe2x80x9cbecome dinosaurs.xe2x80x9d This current flurry of research and media activity makes it clear that a need remains for an anti-inflammatory compound characterized by an ability to selectively block prostaglandin production via the COX-2 pathway.
There is provided in accordance with one aspect of the present invention, a method of treating inflammation in an animal. The method comprises administering to the animal a dose of at least 2.5 milligrams of an enantiomerically pure R-NSAID per kilogram of said animal""s body weight. In other embodiments, the administered dose is at least 5 mg/kg, at least 25 mg/kg, and at least 50 mg/kg of the animals body weight. In preferred embodiments of the methods, the R-NSAID is selected from the group consisting of R-ketoprofen, R-flurbiprofen, R-ketorolac, R-etodolac, R-tiaprofenic acid, R-suprofen, R-carprofen, R-pirprofen, and R-benoxaprofen. In an especially preferred embodiment, the R-NSAID is R-flurbiprofen.
In accordance with a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment of inflammation. The pharmaceutical composition comes in a unit dosage form and comprises at least 200 milligrams of an enantiomerically pure R-NSAID. In other embodiments, the unit dosage form is at least 400 milligrams, at least 1,000 milligrams, and at least 3,500 milligrams. In preferred embodiments, the R-NSAID of the pharmaceutical composition is selected from the group consisting of R-ketoprofen, R-flurbiprofen, R-ketorolac, R-etodolac, R-tiaprofenic acid, R-suprofen, R-carprofen, R-pirprofen, and R-benoxaprofen. In an especially preferred embodiment, the R-NSAID is R-flurbiprofen.